Polyhydroxyalkylpyrazine derivatives, their preparation and the medicaments comprising them

ABSTRACT

The present invention relates to medicaments comprising at least one compound of formula:                    
     wherein 
     either R 1  represents a —CH(Ra)—CHOH—CHOH—CH 2 OH chain and 
     R 2  represents a —CH 2 —CHOH—CHOH—CH 2 OH chain, 
     or R 1  represents a —CHOH—CHF—CHOH—CH 2 OH chain and R 2  represents a —CH 2 —CHF—CHOH—CH 2 OH chain, 
     or R 1  represents a —CHOH—CHOH—CHOH—Rb chain and R 2  represents a —CH 2 —CHOH—CHOH—Rb chain, 
     or R 1  represents a —CH 2 —CHOH—CHOH—CH 2 OH chain and R 2  represents a —CH 2 —CHOH—CHOH—CH 2 OH chain, 
     or R 1  and R 2  are identical and each represent a —(CHOH)n—CH 2 OH chain in which n is equal to 1, 2, 3 or 4, 
     Ra represents an alkoxy radical (1-6 C in a straight or branched chain) or a fluorine atom, and 
     Rb represents a carboxyl, —CO—NH 2  or —CH 2 —NH 2  radical, 
     or one of their stereoisomers or their salts with an inorganic or organic acid, to novel compounds of formula (I) and to their preparation.

This application is a continuation of PCT/FR98/01540 Jul. 15, 1998.

The present invention relates to medicaments comprising, as activeprinciple, at least one compound of formula:

or one of their stereoisomers or their salts with an inorganic ororganic acid, to novel compounds of formula (I) and to theirpreparation.

In the formula (I), either R₁ represents a —CH(Ra)—CHOH—CHOH—CH₂OH chainand

R₂ represents a —CH₂—CHOH—CHOH—CH₂OH chain,

or R₁ represents a —CHOH—CHF—CHOH—CH₂OH chain and R₂ represents a—CH₂—CHF—CHOH—CH₂OH chain,

or R₁ represents a —CHOH—CHOH—CHOH—Rb chain and R₂ represents a—CH₂—CHOH—CHOH—Rb chain,

or R₁ represents a —CH₂—CHOH—CHOH—CH₂OH chain and R₂ represents a—CH₂—CHOH—CHOH—CH₂OH chain,

or R₁ and R₂ are identical and each represent a —(CHOH)n—CH₂OH chain inwhich n is equal to 1, 2, 3 or 4,

Ra represents an alkoxy radical (1-6 C in a straight or branched chain)or a fluorine atom,

Rb represents a carboxyl, —CO—NH₂ or —CH₂—NH₂ radical.

As the compounds of formula (I) comprise several asymmetric carbons,[lacuna] exhibit stereoisomeric forms. These various stereoisomers formpart of the invention.

The compound of formula:

is described in Nippon Shokuhin Kogyo Gakkaishi, 37 (2), 154 (1990),Agric. Biol. Chem., 44 (5), 1189 (1980), Carbohydr. Res., 67 (2), 549(1978).

The compound of formula:

is described in Dev. Food Sci., 13, 85 (1986).

No pharmacological activity is described for these derivatives.

The other compounds of formula (I) are novel and, as such, form part ofthe present invention.

The preferred medicaments are those which comprise, as active principle,at least one of the following compounds:

-4-[6-(2,3,4-Trihydroxybutyl)pyrazin-2-yl]-4-methoxy-butane-1,2,3-triol,

-4-[6-(2,3,4-Trihydroxybutyl)pyrazin-2-yl]-4-fluorobutane-1,2,3-triol,

-1-[6-(2-Fluoro-3,4-dihydroxybutyl)pyrazin-2-yl]-2-fluorobutane-1,3,4-triol,

-1-[6-(2,3-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1,2,3-triol,

-4-[6-(2,3-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2,3,4-trihydroxybutanoicacid,

-4-[6-(2,3-Dihydroxy-4-carbamoylpropyl)pyrazin-2-yl]-2,3,4-trihydroxybutanamide,

-4-[6-(2,3,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2,3-triol,

1-[6-(1,2-Dihydroxyethyl)pyrazin-2-yl]ethane-1,2-diol,

1-[6-(1,2,3-Trihydroxypropyl)pyrazin-2-yl]propane-1,2,3-triol,

1-[6-(1,2,3,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1,2,3,4-tetraol,

1-[6-(1,2,3,4,5-Pentahydroxypentyl)pyrazin-2-yl]-pentane-1,2,3,4S,5-pentaol,

their stereoisomers and their salts with a pharmaceutically acceptableinorganic or organic acid.

The particularly preferred medicaments are those which comprise acompound chosen from the following compounds:

-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-methoxybutane-1,2R,3S-triol,

-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3R-triol,

-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3S-triol,

-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-fluorobutane-1,2R,3R-triol,

-1-[6-(2S-Fluoro-3R,4-dihydroxybutyl)pyrazin-2-yl]-2S-fluorobutane-1R,3R,4-triol,

-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-fluorobutane-1,2R,3R-triol,

-1-[6-(2S,3R-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3R-triol,

-1-[6-(2S,3S-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3S-triol,

-4-[6-(2S,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanoicacid,

-4-[6-(2R,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3R,4R-trihydroxybutanoicacid,

-4-[6-(2S,3S-Dihydroxy-4-carbamoylpropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanamide,

-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3S-triol,

-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3R-triol,

1-[6-(1R,2-Dihydroxyethyl)pyrazin-2-yl]ethane-1R,2-diol,

1-[6-(1S,2-Dihydroxyethyl)pyrazin-2-yl]ethane-1S,2-diol,

1-[6-(1R,2S,3-Trihydroxypropyl)pyrazin-2-yl]propane-1R,2S,3-triol,

1-[6-(1S,2R,3-Trihydroxypropyl)pyrazin-2-yl]propane-1S,2R,3-triol,

1-[6-(1S,2S,3-Trihydroxypropyl)pyrazin-2-yl]propane-1S,2S,3-triol,

1-[6-(1R,2R,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol,

1-[6-(1R,2R,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol,

1-[6-(1R,2S,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol,

1-[6-(1R,2S,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol,

1-[6-(1S,2R,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol,

1-[6-(1S,2R,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol,

1-[6-(1S,2S,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol,

1-[6-(1S,2S,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol,

1-[6-(1R,2R,3R,4S,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2R,3R,4S,5-pentaol,

1-[6-(1R,2S,3S,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2S,3S,4R,5-pentaol,

1-[6-(1R,2S,3R,4S,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2S,3R,4S,5-pentaol,

1-[6-(1R,2R,3R,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2R,3R,4R,5-pentaol,

1-[6-(1R,2S,3R,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2S,3R,4R,5-pentaol,

1-[6-(1S,2R,3R,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1S,2R,3R,4R,5-pentaol,

1-[6-(1S,2R,3S,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1S,2R,3S,4R,5-pentaol,

and their salts with a pharmaceutically acceptable inorganic or organicacid.

The even more particularly preferred medicaments are those whichcomprise a compound chosen from the following compounds:

-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-methoxybutane-1,2R,3S-triol,

-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3R-triol,

-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3S-triol,

-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-fluorobutane-1,2R,3R-triol,

-1-[6-(2s-Fluoro-3R,4-dihydroxybutyl)pyrazin-2-yl]-2S-fluorobutane-1R,3R,4-triol,

-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-fluorobutane-1,2R,3R-triol,

-1-[6-(2S,3R-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3R-triol,

-1-[6-(2S,3S-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3S-triol,

-4-[6-(2S,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanoicacid,

-4-[6-(2R,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3R,4R-trihydroxybutanoicacid,

-4-[6-(2S,3S-Dihydroxy-4-carbamoylpropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanamide,

-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3S-triol,

-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3R-triol,

and their salts with an inorganic or organic acid.

The compounds of formula (I) can be prepared by reaction of ammoniumformate with one or two derivatives of formula:

OHC—CHOH—Rc  (II)

in which Rc represents a —CH(Ra)—CHOH—CHOH—CH₂OH, —CHOH—CHF—CHOH—CH₂OH,—CHOH—CHOH—CHOH—Rb, CH₂—CHOH—CHOH—CH₂OH or —(CHOH)n—CH₂OH chain in whichn is equal to 1, 2, 3 or 4, Ra represents an alkoxy radical (1-6 C as astraight or branched chain) or a fluorine atom and Rb represents acarboxyl, —CO—NH₂ or —CH₂—NH₂ radical, or one of its stereoisomers.

This reaction is generally carried out in aqueous medium, at atemperature of between 20 C. and 100 C.

The derivatives of formula (II) and their stereoisomers are commerciallyavailable or can be obtained from:

a) commercially available aldoses:

by epimerization reactions, by application or adaptation of the methodsdescribed in Adv. Carbohydr. Chem., 13, 63, (1958), in particular inbasic medium by means of a dilute aqueous sodium hydroxide solution(0.03 to 0.05%), at a temperature of between 20 and 40 C.,

by chain-extension reactions, by application or adaptation of themethods described in “The Carbohydrates”, edited by W. Pigman and D.Horton, Academic Press, New York, Volume IA, 133 (1972) and inparticular by forming the cyanohydrin of the starting aldose (forexample, by reaction with sodium cyanide in aqueous solution, at atemperature of between 10 and 30 C. and in the presence of sodiumhydroxide, at a pH in the region of 9), then hydrolysis of the nitrilefunctional group thus formed to the corresponding acid by application oradaptation of the methods described in Organic Synthesis, Volume I, page436 and Volume III, page 85 (for example, using concentrated sulphuricacid or hydrochloric acid, in aqueous solution, at a temperature ofbetween 20 C. and the reflux temperature of the reaction mixture), andthen reduction of the carboxylic acid functional group to thecorresponding aldehyde by application or adaptation of the methodsdescribed in J. Am. Chem. Soc., 71, 122 (1949), in particular using analkali metal borohydride (for example, sodium borohydride), in aqueoussolution, at a temperature of between 20 C. and the boiling temperatureof the reaction mixture,

by chain-shortening reactions, by application or adaptation of themethods described in “The Carbohydrates”, edited by W. Pigman and D.Horton, Academic Press, New York, Volume IB, 1980, page 929 or Chem.Ber., 83, 559 (1950) and in particular by converting the aldehydefunctional group of the aldose to the corresponding hydroxylamine byapplication or adaptation of the methods described in Organic Synthesis,Volume II, page 314 (for example, using hydroxylamine hydrochloride, inaqueous solution and in the presence of a base, such as sodiumcarbonate, at a temperature of between 20 and 50 C.), and then reactionwith 3,4-dinitrofluorobenzene in the presence of carbon dioxide and abase, such as sodium hydrogencarbonate, in aqueous solution, and analiphatic alcohol (for example, isopropyl alcohol), at a temperature ofbetween 50 and 80 C.,

b) corresponding allyl alcohols, by application or adaptation of themethods described in Science, 220, 949 (1983) and in particular usingtert-butyl hydroperoxide in the presence of a titanium (IV) complex,such as the titanium (IV) isopropoxide and optically pure dialkyltartrate (for example, diethyl tartrate) complex, followed by successivereaction with sodium thiophenolate, para-chloroperbenzoic acid in aceticanhydride, and diisopropylaluminium hydride.

The derivatives of formula (II) can also be obtained by application oradaptation of the methods described in J. Am. Chem. Soc., 113 (21), 8137(1991), Chem. Pharm. Bull., 35(7), 2894 (1987), Carbohydr. Res., 154,127 (1986), Sen'i Gakkaihi, 35 (12), 525 (1979), Chem. Ber., 101 (7),2294 (1968), J. Carbohydr. Chem., 3 (2), 219 (1984) and Tetrahedron, 40(12), 2233 (1984) and Patents WO 9310137 and WO 89-US51089029.

The various stereoisomers of the compounds of formula (I) are obtainedfrom the corresponding stereoisomers of the intermediates (II). Use ispreferably made, among these stereoisomers, of3-methoxy-D-glucopyranose, 3-fluoro-3-deoxy-D-glucose,4-fluoro-4-deoxy-D-glucose, 6-amino-6-deoxy-D-glucose, D-glucuronicacid, D-galacturonic acid, D-glucuronamide and 3-deoxy-D-glucose.

It is understood by a person skilled in the art that, for theimplementation of the processes according to the invention describedabove, it may be necessary to introduce protective groups for the amino,hydroxyl and carboxyl functional groups, in order to avoid sidereactions. These groups are those which can be easily removed withoutaffecting the remainder of the molecule. Mention may be made, asexamples of protective groups for the amino functional group, oftert-butyl or methyl carbamates which can be regenerated by means ofiodotrimethylsilane. Mention may be made, as examples of protectivegroups for the hydroxyl functional group, of trialkylsilyl (for example,triethylsilyl) or benzyl. Mention may be made, as protective groups forthe carboxyl functional groups, of esters (for example, methoxymethylester, tetrahydropyranyl ester or benzyl ester), oxazoles and2-alkyl-1,3-oxazolines. Other protective groups which can be used inthese processes are also described by W. Greene et al., ProtectiveGroups in Organic Synthesis, second edition, 1991, John Wiley & Sons andP. J. Kocienski, Protecting Groups, published by Thieme Verlag (1994).

The reaction mixtures obtained by the various processes described aboveare treated according to conventional physical (evaporation, extraction,distillation, chromatography or crystallization, for example) orchemical (formation of salts, for example) methods.

The compounds of formula (I) can optionally be converted to additionsalts with an inorganic or organic acid by the action of such an acid inan organic solvent, such as an alcohol, a ketone, an ether or achlorinated solvent.

These salts also form part of the invention.

Mention may be made, as examples of pharmaceutically acceptable salts,of the addition salts with inorganic or organic acids, such as acetate,propionate, succinate, benzoate, fumarate, maleate, oxalate,methanesulphonate, isethionate, theophyllinacetate, salicylate,methylenebis(β-oxynaphthoate), hydrochloride, sulphate, nitrate andphosphate.

The preferred compounds of formula (I) are those mentioned above asactive principle of the preferred medicaments, with the exception of theknown products.

The following examples illustrate the invention:

EXAMPLE 1

3.2 g of ammonium formate are added to a solution of 2 g of3-methoxy-D-glucopyranose in 3.4 cm³ of distilled water. The reactionmixture is heated at 2 reflux with stirring at a temperature ofapproximately 100 C. for 2 h. After cooling to a temperature ofapproximately 25 C., the mixture is diluted with 25 cm³ of ethyl acetateand separated by settling. The aqueous phase is washed with 25 cm³ ofethyl acetate and then concentrated under reduced pressure (2.7 kPa) ata temperature in the region of 70 C. The residue is taken up in 100 cm³of absolute ethanol and then stirred for 24 h. The precipitate thusobtained is filtered on sintered glass and washed several times withabsolute ethanol and the filtrate is concentrated under reduced pressure(2.7 kPa) at a temperature in the region of 45 C. (operation repeatedonce). The residual oil is chromatographed on a column of 160 g ofsilica (0.02-0.05 mm) eluted with a 1/199 by volume water/ethanolmixture at atmospheric pressure, 10−cm³ fractions being collected. Thefractions containing the expected product are combined and concentratedunder reduced pressure (2.7 kPa) at a temperature in the region of 20 C.4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-methoxybutane-1,2R,3S-triolis thus obtained [¹H N.M.R. spectrum (400 MHz, d6-(CD₃)₂SO, δ in ppm):2.73 and 3.09 (2 dd, respectively J=14 and 9.5 Hz and J=14 and 3 Hz,each 1H, 6α CH₂), 3.34 (s, 3H, OCH₃ at 2α), from 3.30 to 3.55 and from3.55 to 3.70 (2 mts, the 7H corresponding to: 2β CH, 2γ CH, 2δ CH₂O, 6γCH and 6δ CH₂O), 3.79 (mt, 1H, 6β CH), from 4.00 to 5.00 (several broadunresolved peaks, OH), 4.61 (broad s, 1H, 2α CH), 8.39 (s, 1H, ═CH at5), 8.42 (s, 1H, ═CH at 3).

EXAMPLE 2

21 g of ammonium formate are added to a solution of 10 g of L-gulose in28 cm³ of distilled water. The reaction mixture is heated at reflux withstirring at a temperature of approximately 100 C. for 30 minutes. Aftercooling to a temperature of approximately 25 C., the mixture isconcentrated under reduced pressure (2.7 kPa) at a temperature in theregion of 50 C. The residue is taken up 5 times in ethanol and thenreconcentrated under the same conditions and finally taken up in ethanoland stirred for 3 h. The precipitate thus obtained is filtered onsintered glass, washed with diethyl ether and pulled dry. The filtrateis concentrated under reduced pressure (2.7 kPa) at a temperature in theregion of 50 C. The residue is chromatographed on a column of 800 g ofsilica (0.02-0.05 mm) eluted with a 1/19 by volume water/ethanol mixtureat atmospheric pressure, 30-cm³ fractions being collected. The fractionscontaining the expected product are combined and concentrated underreduced pressure (2.7 kPa) at a temperature in the region of 40 C. Theproduct obtained is recrystallized from a water/ethanol mixture and thendried under reduced pressure (2.7 kPa) at a temperature in the region of25 C.1-[6-(1R,2S,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraolis thus isolated. The compounds of formula (I) exhibit advantageouspharmacological properties. They are of hypoglycaemic type.

The hypoglycaemic activity of the compounds of formula (I) wasdetermined with respect to the hyperglycaemic response to the oraladministration of glucose in the normoglycaemic mouse, according to thefollowing protocol:

Swiss albinos mice weighing between 22 and 26 g are left withoutnourishment for 2 hours. At the end of this period, the glycaemia ismeasured and, immediately after, a dose of glucose (2 g/kg) isadministered orally. Thirty minutes later, the glycaemia is once againmeasured. The mice which respond by a hyperglycaemia greater than 170mg/dl are selected and used to detect the hypoglycaemic activity of thecompounds according to the invention.

The mice thus chosen are divided into groups of at least 10 animals.Several groups receive a solution of 3 to 50 mg/kg of the test productin a vehicle, such as water or a mixture of methylcellulose/tween andwater, or vehicle once daily by gastric intubation. The treatment lasts4 days. On the 4th day, after the final treatment, the animals receive adose of glucose (2 g/kg) and the glycaemia is measured 20 to 40 minuteslater. The percentage of inhibition of the hyperglycaemic response tothe administration of glucose is calculated with respect to the responsemeasured in the group treated with the vehicle.

In this test, the compounds according to the invention exhibit apercentage of inhibition of glycaemia of greater than or equal to 10%.

The compounds of general formula (I) according to the invention exhibita low toxicity. Their LD₅₀ is greater than 2000 mg/kg via the oral routein the mouse.

In human therapeutics, these products are useful in the prevention andtreatment of diabetes and in particular type II diabetes (NID diabetes),obese diabetes, diabetes at the age of about fifty, metaplethoricdiabetes, diabetes affecting the elderly and mild diabetes. They can beused as a supplement to insulin therapy in insulin-dependent diabeteswhere they make it possible to gradually reduce the dose of insulin,unstable diabetes, insulin-resistant diabetes, and as a supplement tohypoglycaemic sulphamides when these do not provide a sufficientdecrease in glycaemia. These products can also be used in complicationsof diabetes, such as hyperlipaemias, lipid metabolism disorders,dyslipaemias and obesity. They are also useful in the prevention andtreatment of lesions of atherosclerosis and their complications(coronopathies, myocardial infarction, cardiomyopathies, progression ofthese three complications into left ventricular insufficiency, variousarteriopathies, arterites of the lower limbs with claudication andprogression into ulcers and gangrene, cerebral vascular insufficiencyand its complications and sexual impotence of vascular origin), diabeticretinopathy and all its manifestations (increase in capillarypermeability, capillary thrombosis and dilation, microaneurysms,arteriovenous shunt, venous dilation, punctiform and macularhaemorrhages, exudates, macular oedemas, manifestations of proliferativeretinopathy: neovessels, proliferative retinitis scars, haemorrhages ofthe vitreous body, retinal detachment), diabetic cataract, diabeticneuropathy in its various forms (peripheral polyneuropathies and itsmanifestations, such as paraesthesias, hyperaesthesias and pain,mononeuropathies, radiculopathies, autonomous neuropathies, diabeticamyotrophies), manifestations of diabetic foot (ulcers of the lowerextremities and of the foot), diabetic nephropathy in its two diffuseand nodular forms, atheromatosis (rise in HDL lipoproteins promoting theelimination of cholesterol from the atheroma plaques, decrease in theLDL lipoproteins, decrease in the LDL/HDL ratio, inhibition of oxidationof the LDLs, decrease in plaque adhesiveness), hyperlipaemias anddyslipaemias (hypercholesterolaemias, hypertriglyceridaemias,normalization of the fatty acid level, normalization of uricaemia,normalization of the A and B apoproteins), cataracts, arterialhypertension and its consequences.

The medicaments according to the invention are composed of a compoundaccording to the invention or a combination of these products, in thepure state or in the form of a composition in which it is combined withany other pharmaceutically compatible product, which can be inert orphysiologically active. The medicaments according to the invention canbe employed orally, parenterally, rectally or topically.

As solid compositions for oral administration, there can be usedtablets, pills, powders (gelatin capsules, cachets) or granules. Inthese compositions, the active principle according to the invention ismixed with one or more inert diluents, such as starch, cellulose,sucrose, lactose or silica, under an argon stream. These compositionscan also comprise substances other than the diluents, for example one ormore lubricants such as magnesium stearate or talc, a colorant, acoating (dragees) or a glaze.

As liquid compositions for oral administration, there can be usedpharmaceutically acceptable solutions, suspensions, emulsions, syrupsand elixirs containing inert diluents, such as water, ethanol, glycerol,vegetable oils or liquid paraffin. These compositions can comprisesubstances other than the diluents, for example wetting, sweetening,thickening, flavouring or stabilizing products.

The sterile compositions for parenteral administration can preferably besolutions in aqueous or nonaqueous form, suspensions or emulsions. Assolvent or vehicle, there can be employed water, propylene glycol, apolyethylene glycol, vegetable oils, in particular olive oil, injectableorganic esters, for example ethyl oleate, or other suitable organicsolvents. These compositions can also contain adjuvants, in particularwetting, isotonizing emulsifying, dispersing and stabilizing agents.Sterilization can be performed in several ways, for example byaseptizing filtration, by incorporating sterilizing agents into thecomposition, by irradiation or by heating. They can also be prepared inthe form of sterile solid compositions which can be dissolved at thetime of use in sterile water or any other injectable sterile medium.

The compositions for rectal administration are suppositories or rectalcapsules which contain, in addition to the active product, excipientssuch as cocoa butter, semisynthetic glycerides or polyethylene glycols.

The compositions for topical administration can be, for example, creams,lotions, collyria, collutoria, nose drops or aerosols.

The doses depend on the desired effect, the duration of treatment andthe administration route used; they are generally between 150 mg and 600mg per day via the oral route for an adult with unit doses ranging from50 mg to 200 mg of active substance.

In general, the doctor will determine the appropriate dosage accordingto the age, weight and all other factors specific to the subject to betreated.

The following examples illustrate compositions according to theinvention:

EXAMPLE A

Hard gelatin capsules, with doses of 50 mg of active product, having thefollowing composition are prepared according to the usual technique:

Active product . . . 50 mg

Cellulose . . . 18 mg

Lactose . . . 55 mg

Colloidal silica . . . 1 mg

Sodium carboxymethylstarch . . . 10 mg

Talc . . . 10 mg

Magnesium stearate . . . 1 mg

EXAMPLE B

Tablets, with doses of 50 mg of active product, having the followingcomposition are prepared according to the usual technique:

Active product . . . 50 mg

Lactose . . . 104 mg

Cellulose . . . 40 mg

Polyvidone . . . 10 mg

Sodium carboxymethylstarch . . . 22 mg

Talc . . . 10 mg

Magnesium stearate . . . 2 mg

Colloidal silica . . . 2 mg

Hydroxymethylcellulose, glycerol, titanium oxide (72/3.5/24.5) mixtureqs for 1 finished film-coated tablet containing 245 mg

EXAMPLE C

An injectable solution containing 50 mg of active product having thefollowing composition is prepared:

Active product . . . 50 mg

Benzoic acid . . . 80 mg

Benzyl alcohol . . . 0.06 ml

Sodium benzoate . . . 80 mg

Ethanol at 95% . . . 0.4 ml

Sodium hydroxide . . . 24 mg

Propylene glycol . . . 1.6 ml

Water . . . qs for 4 ml

The invention also relates to the use of the compounds of generalformula (I) in the preparation of pharmaceutical compositions of use inthe treatment or prevention of diabetes and complications of diabetes.

What is claimed is:
 1. A pharmaceutical composition comprising acompound of formula:

in which either (A) R₁ represents a —CH(Ra)—CHOH—CHOH—CH₂OH chain and R₂represents a —CH₂—CHOH—CHOH—CH₂OH chain, or (B) R₁ represents a—CHOH—CHF—CHOH—CH₂OH chain and R₂ represents a —CH₂—CHF—CHOH—CH₂OHchain, or (C) R₁ represents a —CHOH—CHOH—CHOH—Rb chain and R₂ representsa —CH₂—CHOH—CHOH—Rb chain, or (D) R₁ represents a —CH₂—CHOH—CHOH—CH₂OHchain and R₂ represents a —CH₂—CHOH—CHOH—CH₂OH chain, or (E) R₁ and R₂are identical and each represent a —(CHOH)n—CH₂OH chain in which n isequal to 1, 2, 3 or 4, Ra represents an alkoxy radical (1-6 C in astraight or branched chain) or a fluorine atom, and Rb represents acarboxyl, —CO—NH₂ or —CH₂—NH₂ radical, or their stereoisomers or saltswith an inorganic or organic acid.
 2. A pharmaceutical compositionaccording to claim 1 comprising a compound selected from the groupconsisting of:-4-[6-(2,3,4-Trihydroxybutyl)pyrazin-2-yl]-4-methoxybutane-1,2,3-triol,-4-[6-(2,3,4-Trihydroxybutyl)pyrazin-2-yl]-4-fluorobutane-1,2,3-triol,-1-[6-(2-Fluoro-3,4-dihydroxybutyl)pyrazin-2-yl]-2-fluorobutane-1,3,4-triol,-1-[6-(2,3-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1,2,3,4-triol,-4-[6-(2,3-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2,3,4-trihydroxybutanoicacid,-4-[6-(2,3-Dihydroxy-4-carbamoylpropyl)pyrazin-2-yl]-2,3,4-trihydroxybutanamide,-4-[6-(2,3,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2,3-triol,1-[6-(1,2-Dihydroxyethyl)pyrazin-2-yl]ethane-1,2-diol,1-[6-(1,2,3-Trihydroxypropyl)pyrazin-2-yl]propane-1,2,3-triol,1-[6-(1,2,3,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1,2,3,4-tetraol,1-[6-(1,2,3,4,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1,2,3,4S,5-pentaol,their stereoisomers and their salts with a pharmaceutically acceptableinorganic or organic acid.
 3. A pharmaceutical composition according toclaim 1 comprising a compound selected from the group consisting of:-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-methoxybutane-1,2R,3S-triol,-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3R-triol,-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3S-triol,-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-fluorobutane-1,2R,3R-triol,-1-[6-(2S-Fluoro-3R,4-dihydroxybutyl)pyrazin-2-yl]-2S-fluorobutane-1R,3R,4-triol,-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-fluorobutane-1,2R,3R-triol,-1-[6-(2S,3R-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3R-triol,-1-[6-(2S,3S-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3S-triol,-4-[6-(2S,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanoicacid,-4-[6-(2R,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3R,4R-trihydroxybutanoicacid,-4-[6-(2S,3S-Dihydroxy-4-carbamoylpropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanamide,-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3S-triol,-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3R-triol,1-[6-(1R,2-Dihydroxyethyl)pyrazin-2-yl]ethane-1R,2-diol,1-[6-(1S,2-Dihydroxyethyl)pyrazin-2-yl]ethane-1S,2-diol,1-[6-(1R,2S,3-Trihydroxypropyl)pyrazin-2-yl]propane-1R,2S,3-triol,1-[6-(1S,2R,3-Trihydroxypropyl)pyrazin-2-yl]propane-1S,2R,3-triol,1-[6-(1S,2S,3-Trihydroxypropyl)pyrazin-2-yl]propane-1S,2S,3-triol,1-[6-(1R,2R,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol,1-[6-(1R,2R,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol,1-[6-(1R,2S,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol,1-[6-(1R,2S,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol,1-[6-(1S,2R,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol,1-[6-(1S,2R,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol,1-[6-(1S,2S,3R,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol,1-[6-(1S,2S,3S,4-Tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol,1-[6-(1R,2R,3R,4S,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2R,3R,4S,5-pentaol,1-[6-(1R,2S,3S,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2S,3S,4R,5-pentaol,1-[6-(1R,2S,3R,4S,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2S,3R,4S,5-pentaol,1-[6-(1R,2R,3R,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2R,3R,4R,5-pentaol,1-[6-(1R,2S,3R,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1R,2S,3R,4R,5-pentaol,1-[6-(1S,2R,3R,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1S,2R,3R,4R,5-pentaol,1-[6-(1S,2R,3S,4R,5-Pentahydroxypentyl)pyrazin-2-yl]pentane-1S,2R,3S,4R,5-pentaol,and their salts with a pharmaceutically acceptable inorganic or organicacid.
 4. A pharmaceutical composition according to claim 1 comprising acompound selected from the group consisting of:-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-methoxybutane-1,2R,3S-triol,-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3R-triol,-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-methoxybutane-1,2R,3S-triol,-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4R-fluorobutane-1,2R,3R-triol,-1-[6-(2S-Fluoro-3R,4-dihydroxybutyl)pyrazin-2-yl]-2S-fluorobutane-1R,3R,4-triol,-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]-4S-fluorobutane-1,2R,3R-triol,-1-[6-(2S,3R-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3R-triol,-1-[6-(2S,3S-Dihydroxy-4-aminobutyl)pyrazin-2-yl]-4-aminobutane-1R,2R,3S-triol,-4-[6-(2S,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanoicacid,-4-[6-(2R,3S-Dihydroxy-4-carboxypropyl)pyrazin-2-yl]-2S,3R,4R-trihydroxybutanoicacid,-4-[6-(2S,3S-Dihydroxy-4-carbamoylpropyl)pyrazin-2-yl]-2S,3S,4R-trihydroxybutanamide,-4-[6-(2S,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3S-triol,-4-[6-(2R,3R,4-Trihydroxybutyl)pyrazin-2-yl]butane-1,2R,3R-triol, andtheir salts with an inorganic or organic acid.
 5. A compound of formula:

in which either (A) R₁ represents a —CH(Ra)—CHOH—CHOH—CH₂OH chain and R₂represents a —CH₂—CHOH—CHOH—CH₂OH chain, or (B) R₁ represents a—CHOH—CHF—CHOH—CH₂OH chain and R₂ represents a —CH₂—CHF—CHOH—CH₂OHchain, or (C) R₁ represents a —CHOH—CHOH—CHOH—Rb chain and R₂ representsa —CH₂—CHOH—CHOH—Rb chain, or (D) R₁ represents a —CH₂—CHOH—CHOH—CH₂OHchain and R₂ represents a —CH₂—CHOH—CHOH—CH₂OH chain, or (E) R₁ and R₂are identical and each represent a —(CHOH)_(n)—CH₂OH chain in which n isequal to 1, 2, 3 or 4, Ra represents an alkoxy radical (1-6 C in astraight or branched chain) or a fluorine atom, Rb represents acarboxyl, —CO—NH₂ or —CH₂—NH₂ radical, their stereoisomers and theirsalts with an inorganic or organic acid provided, however, that saidcompound is not either of:

or their stereoisomers and their salts with an inorganic or organicacid.
 6. A process for the preparation of a compound according to claim5, said process comprising reacting ammonium formate with one or twocompounds of formula: OHC—CHOH—Rc  (II) in which Rc represents a—CH(Ra)—CHOH—CHOH—CH₂OH, —CHOH—CHF—CHOH—CH₂OH, —CHOH—CHOH—CHOH—Rb,CH₂—CHOH—CHOH—CH₂OH or —(CHOH)n—CH2OH chain in which n is equal to 1, 2,3 or 4, Ra represents an alkoxy radical (1-6 C in a straight or branchedchain) or a fluorine atom and Rb represents a carboxyl, —CO—NH₂ or—CH₂—NH₂ radical, or one of its stereoisomers, and isolating the productand optionally converting the product to a salt with an inorganic ororganic acid.
 7. A method for the treatment of diabetes or complicationsof diabetes, this method comprising administering to a patient in needof such treatment an effective amount of a compound of formula (I)

in which either (A) R₁ represents a —CH(Ra)—CHOH—CHOH—CH₂OH chain and R₂represents a —CH₂—CHOH—CHOH—CH₂OH chain, or (B) R₁ represents a—CHOH—CHF—CHOH—CH₂OH chain and R₂ represents a —CH₂CHF—CHOH—CH₂OH chain,or (C) R₁ represents a —CHOH—CHOH—CHOH—Rb chain and R₂ represents a—CH₂—CHOH—CHOH—Rb chain, or (D) R₁ represents a —CH₂—CHOH—CHOH—CH₂OHchain and R₂ represents a —CH₂—CHOH—CHOH—CH₂OH chain, or (E) R₁ and R₂are identical and each represent a —(CHOH)n—CH₂OH chain in which n isequal to 1, 2, 3 or 4, Ra represents an alkoxy radical (1-6 C in astraight or branched chain) or a fluorine atom, and Rb represents acarboxyl, —CO—NH₂ or —CH₂—NH₂ radical, or its stereoisomers or saltswith an inorganic or organic acid in a pharmaceutically acceptablevehicle.